Dr. Nettles is an infectious disease fellow at Johns Hopkins University who has spent the research years of his fellowship working with his mentors Drs. Siliciano, Gallant, and Moore on the optimization and clinical application of an ultra-sensitive HIV-1 genotype assay. Through this award, Dr. Nettles hopes to conduct basic science research on HIV resistance testing as a faculty member of the Division of Infectious Diseases. To determine the clinical and evolutionary significance of HIV-1 resistance during periods of low-level and rapidly decreasing plasma viral loads, Dr. Nettles plans to develop better methods for monitoring resistance to antiretroviral therapy using novel RT-PCR ultra-sensitive genotypic resistance assays. He proposes to define the predictors, etiology, and consequence of persistent low levels of viremia in Johns Hopkins Moore Clinic patients with and without baseline drug-resistance mutations. Furthermore, he will characterize and determine the significance of intermittent low-level HIV-1 viremia ("blips") in patients on highly active antiretroviral therapy through intense drug level, viral load, and genotypic monitoring supported by a General Clinical Research Center. Finally, he will determine the utility of genotype resistance testing on antiretroviral-experienced patients after reinitiation of antiretroviral therapy at various time points during decay in plasma viral load. We anticipate that this will lead to a better understanding of the most effective use of genotype resistance testing and antiretroviral therapy for the 42 million people currently infected with HIV-1. Since little direct patient contact is anticipated, Dr. Nettles plans to conduct these studies through a K08 award. Dr. Nettles will attend virology and infectious disease seminars as well as courses through the Department of Medicine and School of Public Health. This, along with excellent mentorship and the supportive environment at Johns Hopkins University, will provide Dr. Nettles with the skills he needs to develop into an independent researcher studying HIV resistance.